Targeting Glutamine Metabolism to Prevent Diabetic Cardiovascular Complications

Cardiovascular Complications Clinical Trial

— GLUTADIAB  

Official title:

Targeting Glutamine Metabolism to Prevent Diabetic Cardiovascular Complications

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04353869
• Other study ID #: GLUTADIAB
• Status: Recruiting
• Start date: November 16, 2020
• Est. completion date: January 16, 2024

Study information

• Verified date: November 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Louis POTIER, MD
• Phone: 01 40 25 73 01
• Email: louis.potier[@]aphp.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Experimental data suggest that glutamine catabolism in involved in the activation of macrophages by generating TCA(Tricarboxylic acid) intermediates that promote the pro-inflammatory polarization of macrophages. The project investigates the possible link between glutaminolysis, monocytes polarization and diabetes related cardiovascular complications in humans

Description:

The aim of the study is to investigate the role of glutamine metabolism in the pro-inflammatory activation of macrophages in diabetes and related cardiovascular complications.

The study focuses on 3 adult patients' population with different diabetic status and level of cardiovascular risk:

• Patients with uncomplicated type 1 or type 2 diabetes and low cardiovascular risk

• Patients with uncomplicated type 1 or type 2 diabetes and high cardiovascular risk

• Patients with complicated type 1 or type 2 diabetes

Participants (n=975) will be recruited at clinical sites, in the diabetes and cardiology departments (APHP, Bichat - Claude-Bernard Hospital and APHP, Lariboisière Hospital), over a 2-year period.

The study will consist in a single visit. During a scheduled hospitalization or consultation as part of the follow-up of their diabetes or as part of the follow-up of their cardiological problems, clinical data will be collected as well as additional blood and urine samples for analyses and biobanking. There will be no other intervention specific to the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 975
• Est. completion date: January 16, 2024
• Est. primary completion date: January 16, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria General inclusion criteria applying to the five populations are the following:

• Age above 18 years

• BMI between 25 and 40 kg/m²

Inclusion criteria according to study group are listed below.

Group 1: Patients with uncomplicated diabetes and low cardiovascular risk, additional inclusion criteria are:

• 5 or more years of diabetes

• 6% < HbA1c < 10%

• no history of cardiovascular event, diabetic microvascular complications (kidney function normal and albuminuria/creatininuria < 30 mg/g)

• Coronary artery calcium score < 100 (assessment < 12 months)

Group 2: Patients with uncomplicated diabetes and high cardiovascular risk, additional inclusion criteria are:

• 5 or more years of diabetes

• 6% < HbA1c < 10%

• no history of cardiovascular eventand diabetic nephropathy no more than stage 2 (i.e. GFR = 60 ml/min by MDRD or CKD-EPI formula and albuminuria/creatininuria = 30 mg/g)

• Coronary artery calcium score > 400 (assessment < 12 months)

Group 3: Patients with complicated diabetes, additional inclusion criteria are:

• 5 or more years of diabetes

• 6% < HbA1c < 10%

• A history of cardiovascular event (myocardial infarction, stroke, peripheral vascular disease, or angioplasty) at least 3 months ago

Exclusion Criteria:

• Solid organ or bone marrow transplant patient

• Pregnant or breastfeeding woman

• Absence of free and informed consent

• Non-affiliation to a social security regimen or CMU (universal health coverage)

• Subject deprived of freedom, subject under a legal protective measure

Related Conditions & MeSH terms

• Cardiovascular Complications
• Diabetic
• Glutamine

Intervention

Biological:
• Bio collection
venous blood sampling and collection of urine

Locations

Country	Name	City	State
France	Diabétologie - Hôpital Lariboisière	Paris
France	Diabetologie Bichat	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	National Research Agency, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Compare the plasma concentrations of glutamine in patients with various levels of cardiovascular (CV) risk.	plasma concentration of glutamine in each subject.	DAY 1
Secondary	Study glutamine metabolism in patients with various levels of CV risk	plasma concentration of glutamate in each treatment group	DAY 1
Secondary	Study glutamine metabolism in patients with various levels of CV risk	plasma concentration of a-ketoglutarate, fumarate, and succinate in each treatment group	DAY1
Secondary	Study glutamine metabolism in patients with various levels of CV risk	monocyte cytoplasmic concentration of a-ketoglutarate, fumarate and succinate in each treatment group	DAY 1
Secondary	study the inflammatory status in patients with various levels of CV risk	plasma concentration of VEGF (Vascular endothelial growth factor) in each treatment group	DAY 1
Secondary	study the inflammatory status in patients with various levels of CV risk	plasma concentration of the proinflammatory cytokines IL-1, IL-6, IL-8 (interleukin) and TNF-a (Tumor Necrosis Factor alpha)	DAY 1
Secondary	study the inflammatory status in patients with various levels of CV risk	blood concentration of circulating PBMCs (peripheral blood mononuclear cell)	DAY 1
Secondary	study the monocyte activation status in patients with various levels of CV risk	frequency of monocyte subsets (CD14++CD16+, CD14++CD16++, CD14+CD16++)	DAY 1
Secondary	characterize the transcriptomic program through modification gene expression and epigenetic changes related to KDM6B (Lysine Demethylase 6B) and TET2 (Ten-eleven-translocation 2) activity in blood monocytes from patients with various levels of CV risk	Number of transcript for each gene	DAY 1
Secondary	characterize the transcriptomic program through modification gene expression and epigenetic changes related to KDM6B and TET2 activity in blood monocytes from patients with various levels of CV risk	Number of methylated gene loci and their proportion of methylation	DAY 1
Secondary	characterize the transcriptomic program through modification gene expression and epigenetic changes related to KDM6B and TET2 activity in blood monocytes from patients with various levels of CV risk	Frequency and level of histone H3K27me (Methylation of lysine 27 on histone H3) methylation	DAY 1